A candidate molecular signature associated with tamoxifen failure in primary breast cancer.
BACKGROUND
Few markers are available that can predict response to tamoxifen treatment in estrogen receptor (ER)-positive breast cancers. Identification of such markers would be clinically useful. We attempted to identify molecular markers associated with tamoxifen failure in breast cancer.


METHODS
Eighteen initially ER-positive patients treated with tamoxifen requiring salvage surgery (tamoxifen failure [TF] patients) were compared with 17 patients who were disease free 5 years after surgery plus tamoxifen adjuvant therapy (control patients). cDNA microarray, real-time quantitative PCR, and immunohistochemistry on tissue microarrays were used to generate and confirm a gene signature associated with tamoxifen failure. An independent series of 33 breast tumor samples from patients who relapsed (n = 14) or did not relapse (n = 19) under tamoxifen treatment from a different geographic location was subsequently used to explore the gene expression signature identified.


RESULTS
Using a screening set of 18 tumor samples (from eight control patients and 10 TF patients), a 47-gene signature discriminating between TF and control samples was identified using cDNA arrays. In addition to ESR1/ERalpha, the top-ranked genes selected by statistical cross-analyses were MET, FOS, SNCG, IGFBP4, and BCL2, which were subsequently validated in a larger set of tumor samples (from 17 control patients and 18 TF patients). Confirmation at the protein level by tissue microarray immunohistochemistry was observed for ER-alpha, gamma-synuclein, and insulin-like growth factor binding protein 4 proteins in the 35 original samples. In an independent series of breast tumor samples (19 nonrelapsing and 14 relapsing), reduced expression of ESR1/ERalpha, IGFBP4, SNCG, BCL2, and FOS was observed in the relapsing group and was associated with a shorter overall survival. Low mRNA expression levels of ESR1/ERalpha, BCL2, and FOS were also associated with a shorter relapse-free survival (RFS). Using a Cox multivariate regression analysis, we identified BCL2 and FOS as independent prognostic markers associated with RFS. Finally, the BCL2/FOS signature was demonstrated to have more accurate prognostic value for RFS than ESR1/ERalpha alone (likelihood ratio test).


CONCLUSIONS
We identified molecular markers including a BCL2/FOS signature associated with tamoxifen failure; these markers may have clinical potential in the management of ER-positive breast cancer.
Vendrell
Julie A
JA
Université de Lyon, Faculté de Pharmacie de Lyon, France.
Robertson
Katherine E
KE
Ravel
Patrice
P
Bray
Susan E
SE
Bajard
Agathe
A
Purdie
Colin A
CA
Nguyen
Catherine
C
Hadad
Sirwan M
SM
Bieche
Ivan
I
Chabaud
Sylvie
S
Bachelot
Thomas
T
Thompson
Alastair M
AM
Cohen
Pascale A
PA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use*; D015415:Biomarkers; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000601:surgery; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000601:surgery; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D020847:Estrogen Receptor Modulators / Q000494:pharmacology / Q000627:therapeutic use*; D004967:Estrogens; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis / Q000235:genetics*; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000235:genetics / Q000601:surgery; D020411:Oligonucleotide Array Sequence Analysis; D016016:Proportional Hazards Models; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D011960:Receptors, Estrogen / Q000032:analysis; D016879:Salvage Therapy; D013629:Tamoxifen / Q000494:pharmacology / Q000627:therapeutic use*; D017211:Treatment Failure
D018931:Antineoplastic Agents, Hormonal; D015415:Biomarkers; D020847:Estrogen Receptor Modulators; D004967:Estrogens; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011960:Receptors, Estrogen; D013629:Tamoxifen